PROJECT SUMMARY/ABSTRACT: As a physician-scientist in the field of neuropathology, I have a strong interest in diseases of the brain, particularly those associated with neuronal dysfunction and degeneration. My long-term career goal is to understand the molecular mechanisms that underlie some of the most common neurodegenerative diseases, such as Alzheimer's disease (AD), and to translate that knowledge into clinically relevant therapeutics. In my recent studies of neurodevelopment, I discovered multiple connections between developmental processes and neurodegeneration, and I decided to shift direction to explore those connections. Since I have not previously worked in this research area, I have designed an intensive training program to gain expertise and facilitate my transition to this important field. Under the mentorship of Dr. Lennart Mucke, a leading authority on AD pathogenesis, my research program will address the hypothesis that integrin signaling plays a critical role in the progression of AD by altering amyloid dynamics and glutamate receptor trafficking of mature neurons. I will use a variety of genetic methods to alter integrin signaling in cultured cells and mouse models and examine the resulting effects on neurotoxicity and the accumulation, aggregation and endocytosis of amyloid-2 (A2) oligomers. I will also assess the effect of altered integrin signaling on A2-mediated changes in dendritic spine and synaptic morphology and glutamate receptor localization. As part of these studies, I will generate mouse models of AD on a background of integrin-linked kinase (Ilk) deletion and assess these mice for plaque formation, synaptic function, network excitability, and behavior. Ilk mediates the functions of most integrin heterodimers implicated in AD, and focusing on this adaptor protein will serve to broadly survey the function of integrins in AD. This work promises to yield important insights into the fundamental biology underlying neurodegeneration and integrin signaling in the adult brain. In addition, this proposal is designed to complement my prior laboratory experiences and provide me with the technical and intellectual tools to become an independent investigator. The Gladstone Institutes and the UCSF Pathology Department are fully committed to making all necessary resources available to facilitate the successful completion of this work. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE: There are no disease-modifying therapies for AD, and new approaches to drug discovery are urgently needed. Integrins are a potential new area for AD drug discovery efforts. In particular, the role of integrins in cognitive function suggests that modulating integrin signaling may delay the loss of neuronal connections early in the disease process. My studies promise to reveal the mechanisms by which integrins contribute to AD pathogenesis and to open the way for future drug discovery efforts.